Serum levels of doxycycline in normal subjects after a single oral dose.

Adadevoh, B. Kwaku; Ogunnaike, I A; Bolo-Deoku, J

doi:10.1136/bmj.1.6014.880

Cited by 14 publications

(6 citation statements)

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“…Finally, this work suggests the possibility of repurposing DOX as a faster-acting antiparasitic treatment at higher dosing, whose multiple mechanisms would be expected to limit parasite resistance. Prior studies indicate that 500–600 mg doses in humans achieve sustained serum DOX concentrations ≥ 5 µM for 24–48 hr with little or no increase in adverse effects ( Marlin and Cheng, 1979 ; Adadevoh et al, 1976 ). DOX is currently contraindicated for long-term prophylaxis in pregnant women and young children, two of the major at-risk populations for malaria, due to concerns about impacts on fetal development and infant tooth discoloration, respectively, based on observed toxicities for other tetracyclines ( Gaillard et al, 2018 ).…”

Section: Discussionmentioning

confidence: 99%

Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity

Okada

Guo

Nalder

et al. 2020

eLife

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Doxycycline (DOX) is a key antimalarial drug thought to kill Plasmodium parasites by blocking protein translation in the essential apicoplast organelle. Clinical use is primarily limited to prophylaxis due to delayed second-cycle parasite death at 1-3 µM serum concentrations. DOX concentrations >5 µM kill parasites with first-cycle activity but have been ascribed to off-target mechanisms outside the apicoplast. We report that 10 µM DOX blocks apicoplast biogenesis in the first cycle and is rescued by isopentenyl pyrophosphate, an essential apicoplast product, confirming an apicoplast-specific mechanism. Exogenous iron rescues parasites and apicoplast biogenesis from first- but not second-cycle effects of 10 µM DOX, revealing that first-cycle activity involves a metal-dependent mechanism distinct from the delayed-death mechanism. These results critically expand the paradigm for understanding the fundamental antiparasitic mechanisms of DOX and suggest repurposing DOX as a faster-acting antimalarial at higher dosing whose multiple mechanisms would be expected to limit parasite resistance.

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Section: Discussionmentioning

confidence: 99%

Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity

Okada

Guo

Nalder

et al. 2020

eLife

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“…Tetracyclines are used extensively in tetracycline-controlled transcriptional activation studies [ 22 ]. Blood doxycycline concentrations between 5 and 15 μg/mL have been reported in humans [ 23 , 24 ], but can accumulate in tissue several-fold [ 25 ]. Detailed pharmacokinetics after long-term use in humans are unknown.…”

Section: Introductionmentioning

confidence: 99%

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

Wüst

Coolen

Held

et al. 2021

IJMS

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Tetracycline antibiotics act by inhibiting bacterial protein translation. Given the bacterial ancestry of mitochondria, we tested the hypothesis that doxycycline—which belongs to the tetracycline class—reduces mitochondrial function, and results in cardiac contractile dysfunction in cultured H9C2 cardiomyoblasts, adult rat cardiomyocytes, in Drosophila and in mice. Ampicillin and carbenicillin were used as control antibiotics since these do not interfere with mitochondrial translation. In line with its specific inhibitory effect on mitochondrial translation, doxycycline caused a mitonuclear protein imbalance in doxycycline-treated H9C2 cells, reduced maximal mitochondrial respiration, particularly with complex I substrates, and mitochondria appeared fragmented. Flux measurements using stable isotope tracers showed a shift away from OXPHOS towards glycolysis after doxycycline exposure. Cardiac contractility measurements in adult cardiomyocytes and Drosophila melanogaster hearts showed an increased diastolic calcium concentration, and a higher arrhythmicity index. Systolic and diastolic dysfunction were observed after exposure to doxycycline. Mice treated with doxycycline showed mitochondrial complex I dysfunction, reduced OXPHOS capacity and impaired diastolic function. Doxycycline exacerbated diastolic dysfunction and reduced ejection fraction in a diabetes mouse model vulnerable for metabolic derangements. We therefore conclude that doxycycline impairs mitochondrial function and causes cardiac dysfunction.

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“…The half-life absorption ranges from 1 to 2 hours when administrated while fasting [175], and the peak concentration varies with dose, being 15.3mg/L (~30 μM) after an oral dose of 500mg [176]. Regarding tissue penetration, doxycycline levels are poor in saliva, below those of serum in bone, skin, fat, tendons and muscle [172,177], and highest in the liver, kidney and digestive tract [173].…”

Section: Doxycyline: Pharmacokinetics Pharmacodynamics and Adverse Ementioning

confidence: 99%

Effect of Doxycycline on Atherosclerosis: From Bench to Bedside

Rodríguez-Granillo

Rodriguez-Granillo²,

Milei³

2011

PRC

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Matrix metalloproteinases (MMPs) have a pivotal role in the natural history of atherosclerosis and its cardiovascular consequences. Non-selective MMP inhibition with doxycycline appears as a potential strategy to reduce the residual risk observed in patients already at intensive lipid lowering strategies. However, specific MMPs have different and even contradicting roles in the natural history of atherosclerosis, rendering broad spectrum MMP inhibition an important yet somewhat simplistic approach towards residual risk reduction in coronary atherosclerosis. Overall, the balance of non-selective MMP inhibition might shift to the favorable side in particular settings such as in acute coronary syndromes, where in addition to its potential plaque stabilization properties, doxycycline shows promise in preventing ischemia-reperfusion injury and left ventricular remodeling. Nevertheless, to date, most animal models used do not represent advanced coronary atherosclerosis seen in humans, and large and well-designed clinical studies are lacking. We discuss the available evidence and recent patents supporting the role of doxycycline in atherosclerosis.

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Serum levels of doxycycline in normal subjects after a single oral dose.

Cited by 14 publications

References 1 publication

Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity

Doxycycline has distinct apicoplast-specific mechanisms of antimalarial activity

The Antibiotic Doxycycline Impairs Cardiac Mitochondrial and Contractile Function

Effect of Doxycycline on Atherosclerosis: From Bench to Bedside

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